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1.  Genomic Methylation Changes Over Time in Peripheral Blood Mononuclear Cell DNA: Differences by Assay Type and Baseline Values 
Background
Lower levels of genomic DNA methylation in blood DNA has been associated with risk of different cancers and several cancer risk factors. To understand the use of genomic methylation measures as biomarkers of cancer risk, data are needed on within-individual changes over time.
Methods
Using information from 77 subjects with blood collected at 2 visits on average 8 years apart, we examined whether levels of DNA methylation change with time and if so, whether selected cancer risk factors predict these changes. We measured DNA methylation levels in peripheral blood mononuclear cells (PBMC) using three assays that have been used in epidemiologic studies: (i) luminometric methylation assay (LUMA)(ii) LINE-1 by pyrosequencing, and (iii) Sat2 by MethyLight.
Results
Close to a third of all individuals had large changes over time (≥10%) in LUMA with 19.5% increasing and 13.0% decreasing. For Sat2, two-thirds of individuals had large changes with 40% increasing and 26% decreasing over time. In contrast, only 3.9% of individuals had large changes in LINE-1 over time. The degree of change in PBMC DNA methylation was statistically significantly inversely associated with methylation levels at baseline; greater decreases were observed in individuals with higher baseline values for each assay.
Conclusions
These data, if replicated, suggest that changes in DNA methylation over time are highly associated with baseline values of the assay and vary by assay type.
Impact
These findings suggest that assays that change more over time may warrant consideration for studies that measure later life exposures.
doi:10.1158/1055-9965.EPI-12-0300
PMCID: PMC4032622  PMID: 22665578
2.  Early Developmental Elevations of Brain Kynurenic Acid Impair Cognitive Flexibility in Adults: Reversal with Galantamine 
Neuroscience  2013;238:19-28.
Levels of kynurenic acid (KYNA), an endogenous α7 nicotinic acetylcholine receptor (α7nAChR) antagonist, are elevated in the brain of patients with schizophrenia (SZ) and might contribute to the pathophysiology and cognitive deficits seen in the disorder. As developmental vulnerabilities contribute to the etiology of SZ, we determined, in rats, the effects of perinatal increases in KYNA on brain chemistry and cognitive flexibility. KYNA’s bioprecursor L-kynurenine (100 mg/day) was fed to dams from gestational day 15 (GD15) to postnatal day 21 (PD21). Offspring were then given regular chow until adulthood. Control rats received unadulterated mash. Brain tissue levels of KYNA were measured at PD2 and PD21, and extracellular levels of KYNA and glutamate were determined by microdialysis in the prefrontal cortex in adulthood (PD56-80). In other adult rats, the effects of perinatal L-kynurenine administration on cognitive flexibility were assessed using an attentional set-shifting task. L-Kynurenine treatment raised forebrain KYNA levels ~3-fold at PD2 and ~2.5-fold at PD21. At PD56-80, extracellular prefrontal KYNA levels were moderately but significantly elevated (+12%), whereas extracellular glutamate levels were not different from controls. Set-shifting was selectively impaired by perinatal exposure to L-kynurenine, as treated rats acquired the discrimination and intra-dimensional shift at the same rate as controls, yet exhibited marked deficits in the initial reversal and extra-dimensional shift. Acute administration of the α7nAChR positive modulator galantamine (3.0 mg/kg, i.p.) restored performance to control levels. These results validate early developmental exposure to L-kynurenine as a novel, naturalistic animal model for studying cognitive deficits in SZ.
doi:10.1016/j.neuroscience.2013.01.063
PMCID: PMC3622758  PMID: 23395862
schizophrenia; kynurenine; set-shifting; prefrontal cortex; glutamate; α7 nicotinic receptors
3.  Broad-Spectrum Transgenic Resistance against Distinct Tospovirus Species at the Genus Level 
PLoS ONE  2014;9(5):e96073.
Thrips-borne tospoviruses cause severe damage to crops worldwide. In this investigation, tobacco lines transgenic for individual WLm constructs containing the conserved motifs of the L RNA-encoded RNA-dependent RNA polymerase (L) gene of Watermelon silver mottle virus (WSMoV) were generated by Agrobacterium-mediated transformation. The WLm constructs included: (i) translatable WLm in a sense orientation; (ii) untranslatable WLmt with two stop codons; (iii) untranslatable WLmts with stop codons and a frame-shift; (iv) untranslatable antisense WLmA; and (v) WLmhp with an untranslatable inverted repeat of WLm containing the tospoviral S RNA 3′-terminal consensus sequence (5′-ATTGCTCT-3′) and an NcoI site as a linker to generate a double-stranded hairpin transcript. A total of 46.7–70.0% transgenic tobacco lines derived from individual constructs showed resistance to the homologous WSMoV; 35.7–100% plants of these different WSMoV-resistant lines exhibited broad-spectrum resistance against four other serologically unrelated tospoviruses Tomato spotted wilt virus, Groundnut yellow spot virus, Impatiens necrotic spot virus and Groundnut chlorotic fan-spot virus. The selected transgenic tobacco lines also exhibited broad-spectrum resistance against five additional tospoviruses from WSMoV and Iris yellow spot virus clades, but not against RNA viruses from other genera. Northern analyses indicated that the broad-spectrum resistance is mediated by RNA silencing. To validate the L conserved region resistance in vegetable crops, the constructs were also used to generate transgenic tomato lines, which also showed effective resistance against WSMoV and other tospoviruses. Thus, our approach of using the conserved motifs of tospoviral L gene as a transgene generates broad-spectrum resistance against tospoviruses at the genus level.
doi:10.1371/journal.pone.0096073
PMCID: PMC4014477  PMID: 24811071
4.  Preliminary X-ray crystallographic studies of an N-terminal domain of unknown function from a putative glycosyltransferase from Streptococcus parasanguinis  
A streptococcal domain of unknown function 1792 has been crystallized.
Serine-rich repeat glycoproteins (SRRPs) belong to a growing family of bacterial adhesins; they play important roles in bacterial virulence. Fap1, the first SRRP protein to be identified, is glycosylated; while the first two steps of its glycosylation have been determined, the remaining glycosylation steps are unknown. In a search for proteins that might be relevant to the glycosylation of Fap1, a putative glycosyltransferase (GalT1) from Streptococcus parasanguinis was identified. GalT1 possesses a domain of unknown function at the N-terminus. This domain is highly conserved in bacteria and is a member of a broad superfamily. However, the structure of this domain has not been determined. Here, the conditions used to produce a recombinant version of this protein domain and to grow protein crystals are reported. The crystals obtained belonged to space group C2, with unit-cell parameters a = 71.0, b = 45.1, c = 78.6 Å, β = 109.6°, and diffracted to 1.55 Å resolution at a synchrotron X-ray source. This domain does not share sequence identity with proteins of known structures above a level of 12%.
doi:10.1107/S1744309113007161
PMCID: PMC3660891  PMID: 23695567
DUF1792; glycosyltransferase; Streptococcus parasanguinis
5.  Reducing cannabinoid abuse and preventing relapse by enhancing endogenous brain levels of kynurenic acid 
Nature neuroscience  2013;16(11):10.1038/nn.3540.
In the reward circuitry of the brain, alpha-7-nicotinic acetylcholine receptors (α7nAChRs) modulate effects of delta-9-tetrahydrocannabinol (THC), marijuana’s main psychoactive ingredient. Kynurenic acid (KYNA) is an endogenous negative allosteric modulator of α7nAChRs. Here we report that the kynurenine 3-monooxygenase (KMO) inhibitor Ro 61-8048 increases brain KYNA levels and attenuates cannabinoid-induced increases in extracellular dopamine in reward-related brain areas. In the self-administration model of drug abuse, Ro 61-8048 reduced the rewarding effects of THC and the synthetic cannabinoid WIN 55,212-2 in squirrel monkeys and rats, respectively, and it also prevented relapse to drug-seeking induced by re-exposure to cannabinoids or cannabinoid-associated cues. The effects of enhancing endogenous KYNA levels with Ro 61-8048 were prevented by positive allosteric modulators of α7nAChRs. Despite a clear need, there are currently no medications approved for treatment of marijuana dependence. Modulation of KYNA provides a novel pharmacological strategy for achieving abstinence from marijuana and preventing relapse.
doi:10.1038/nn.3540
PMCID: PMC3835353  PMID: 24121737
6.  Factors affecting long-term survival in elderly patients undergoing radiotherapy for esophageal carcinoma 
Molecular and Clinical Oncology  2014;2(4):571-574.
This study was conducted with the aim to analyze the factors affecting the 1-, 3- and 5-year survival rate of elderly patients with esophageal carcinoma. Between 2004 and 2008, a total of 371 patients aged ≥70 years treated with radiotherapy alone were enrolled in this study. The clinical characteristics and radiotherapy dose were evaluated by survival rate and the 1-, 3- and 5-year overall survival (OS) rates were found to be 42, 13.2 and 9.16%, respectively. The univariate analysis revealed significant differences in T, N, M and clinical stage and radiotherapy dose (all P-values <0.05) and no significant differences in gender (all P-values >0.05). There was a difference in tumor location when only comparing the 3- and 5-year OS rates (P=0.031 and P=0.025, respectively). The multivariate analysis identified clinical stage as an independent factor for the 1-year OS rate (P=0.003), whereas radiotherapy dose and clinical stage were found to be independent factors for the 3- and 5-year OS rates (all P-values 0.05). In the analysis of radiotherapy dose, we observed no significant difference in the 1-year OS rate between the radiation dose (DT) >60 Gy and the 50 Gy≤DT<60 Gy groups (P=0.363); however, there were statistically significant differences in the 3-year OS rate between the 50 Gy≤DT<60 Gy and the other groups (P=0.039 and P=0.032); there were no significant differences in the 5-year OS rate among the dose groups (all P-values >0.05). In conclusion, according to the findings of this retrospective study, radiotherapy alone for elderly patients with esophageal cancer does not appear to be acceptable and there is a need for a more effective treatment. T, N, M and clinical stage and radiotherapy dose were identified as factors significantly affecting the 1-, 3- and 5-year OS in elderly patients with esophageal carcinoma, although a higher radiotherapy dose with normal fractionation did not appear to improve the OS rate.
doi:10.3892/mco.2014.285
PMCID: PMC4051554  PMID: 24940497
elderly; esophageal carcinoma; long-term survival; radiotherapy
7.  Characterization of Nitrite Degradation by Lactobacillus casei subsp. rhamnosus LCR 6013 
PLoS ONE  2014;9(4):e93308.
Nitrites are potential carcinogens. Therefore, limiting nitrites in food is critically important for food safety. The nitrite degradation capacity of Lactobacillus casei subsp. rhamnosus LCR 6013 was investigated in pickle fermentation. After LCR 6013 fermentation for 120 h at 37°C, the nitrite concentration in the fermentation system was significantly lower than that in the control sample without the LCR 6013 strain. The effects of NaCl and Vc on nitrite degradation by LCR 6013 in the De Man, Rogosa and Sharpe (MRS) medium were also investigated. The highest nitrite degradations, 9.29 mg/L and 9.89 mg/L, were observed when NaCl and Vc concentrations were 0.75% and 0.02%, respectively in the MRS medium, which was significantly higher than the control group (p ≤ 0.01). Electron capture/gas chromatography and indophenol blue staining were used to study the nitrite degradation pathway of LCR 6013. The nitrite degradation products contained N2O, but no NH4+The LCR 6013 strain completely degraded all NaNO2 (50.00 mg/L) after 16 h of fermentation. The enzyme activity of NiR in the periplasmic space was 2.5 times of that in the cytoplasm. Our results demonstrated that L. casei subsp. rhamnosus LCR 6013 can effectively degrade nitrites in both the pickle fermentation system and in MRS medium by NiR. Nitrites are degraded by the LCR 6013 strain, likely via the nitrate respiration pathway (NO2−>NO−>N2O−>N2), rather than the aammonium formation pathway (dissimilatory nitrate reduction to ammonium, DNRA), because the degradation products contain N2O, but not NH4+.
doi:10.1371/journal.pone.0093308
PMCID: PMC3995639  PMID: 24755671
8.  Agreement between parents and adolescents on emotional and behavioral problems and its associated factors among Chinese school adolescents: a cross-sectional study 
BMC Psychiatry  2014;14:114.
Background
Most studies about informant agreements on adolescents’ emotional and behavioral problems have been conducted in Western countries, but this subject has not been well researched in China. The aim of this study was to evaluate the pattern of parent–adolescent agreement on adolescents’ problems and its associated factors among school-age adolescents in China.
Methods
This cross-sectional study was conducted in November and December of 2010. A questionnaire including the Child Behavior Checklist (CBCL), the Youth Self-Report (YSR), the Family Environment Scale (FES) and the characteristics of the child (age and gender), parents (parent–adolescent relationship and parental expectations) and family (family structure, negative life events) was distributed to our study population. A total of 2,199 Chinese adolescents (aged 11–18) from 15 public schools in Liaoning Province, who completed the questionnaire, became our final participants. Pearson’s correlation coefficient was used to assess parent–adolescent agreement, and linear regression analysis was used to explore the associated factors of parent–adolescent discrepancies on emotional and behavioral problems.
Results
The parent–adolescent agreement on emotional and behavioral problems was high (mean r = 0.6). The scores of YSR were higher than those of CBCL. Factors that increased informant discrepancies on emotional and behavioral problems were boys, older age, the experience of negative life events, low levels of cohesion and organization, and high levels of conflict in the family.
Conclusions
A high level of parent–adolescent agreement on emotional and behavioral problems was found. Adolescents reported more problems than their parents did. Family environment is an important factor to be considered when interpreting informant discrepancies on the mental health of Chinese adolescents.
doi:10.1186/1471-244X-14-114
PMCID: PMC3991878  PMID: 24735388
School adolescent; Emotional and behavioral problem; Agreement; China; Cross-sectional survey
9.  Plasma Sphingolipids as Potential Indicators of Hepatic Necroinflammation in Patients with Chronic Hepatitis C and Normal Alanine Aminotransferase Level 
PLoS ONE  2014;9(4):e95095.
Accurate estimation of hepatic necroinflammation caused by chronic hepatitis C (CHC) is crucial for prediction of prognosis and design of therapeutic strategy, which is particularly true for CHC patients with normal alanine aminotransferase (ALT) level. Recent studies have shown that sphingolipids have a close relationship with hepatitis C virus infection. The present study aimed to identify plasma sphingolipids related to hepatic necroinflammation. We included 120 treatment-naïve CHC patients and 64/120 had normal ALT levels (<40 U/L). CHC patients who underwent liver biopsies were subjected to Scheuer scoring analysis for scope of hepatic inflammation. Plasma sphingolipids were detected by high-performance liquid chromatography tandem mass spectrometry. Our results showed 44 plasma sphingolipids were detected altogether. Of all detected sphingolipids, hexosylceramide (HexCer) (d18∶1/22∶0) and HexCer (d18∶1/24∶0) showed a significant difference among G0/G1, G2, and G3/G4 (P<0.05). For identifying hepatic necroinflammation (G≥2), after adjusting other factors, the odds ratio (OR) of HexCer (d18∶1/22∶0) reached 1.01 (95% confidence interval [CI]: 1.00–1.02). Furthermore, the area under the curve (AUC) of HexCer (d18∶1/22∶0) was 0.7 (P = 0.01) and approached that of ALT (AUC = 0.78). However, in CHC patients with normal ALT, HexCer (d18∶1/22∶0) was an independent factor (OR: 1.02, 95% CI: 1.01–1.03) to identify the hepatic necroinflammation (G≥2). HexCer (d18∶1/22∶0) not only showed the largest AUC (0.78, P = 0.001), but also exhibited the highest specificity of all indicators. These results indicate that plasma HexCer (d18∶1/22∶0) is a potential indicator to distinguish hepatic necroinflammation in CHC patients. For CHC with normal ALT, the ability of HexCer (d18∶1/22∶0) to distinguish hepatic necroinflammation might be superior to conventional serum indicators.
doi:10.1371/journal.pone.0095095
PMCID: PMC3988168  PMID: 24736528
10.  Serum Response Factor Regulates Bone Formation via IGF-1 and Runx2 Signals 
Serum response factor (SRF) plays vital roles in numerous cellular processes; however, the physiological function of SRF in skeletal tissue remains unknown. In several organ systems, SRF regulates the expression of insulin-like growth factor-1 (IGF-1), which is crucial for normal development of mineralized skeleton and bone remodeling throughout life. Here, we show that conditional deletion of SRF in osteoblasts by osteocalcin-Cre generated viable mice with normal body size and body weight. Compared with normal siblings, osteoblast-specific SRF-deficient adult mice exhibited a marked decrease in bone mineral density and bone formation rate. Deletion of SRF in primary mouse calvarial osteoblasts reduced cell differentiation and mineralization in vitro. This was accompanied by a decrease in IGF-1 expression and secretion. Addition of IGF-1 in the culture media enhanced osteoblast differentiation in control cells and partially restored the mineralization defect of SRF-deficient cells, supporting an important role of SRF in regulating IGF-1 and IGF-1-mediated osteoblast differentiation. IGF-1-induced Akt activation was inhibited in SRF-deficient calvarial cells and enhanced in the SRF overexpressed cells. In addition, SRF deficiency decreased the transcriptional activity of Runx2, the key transcription factor for osteogenesis. Overexpression of SRF induced Runx2 transactivity in control cells and restored Runx2 transactivity in the SRF-deficient cells. Taken together, we conclude that SRF is important for IGF-1-induced osteoblast differentiation and mineralization via regulating IGF-1 expression and Runx2 transactivity.
doi:10.1002/jbmr.1607
PMCID: PMC3977219  PMID: 22434656
Serum Response Factor; Insulin-Like Growth Factor; Akt; Runx2; Osteoblasts
11.  Inhibition of ovarian cancer cell proliferation by Pien Tze Huang via the AKT-mTOR pathway 
Oncology Letters  2014;7(6):2047-2052.
Pien Tze Huang (PZH) is a well-known Chinese medicine that has been used as a therapeutic drug in the treatment of a number of diseases, such as hepatocellular carcinoma and colon cancer. However, few studies have analyzed the effects of PZH on ovarian cancer cell proliferation. In the present study, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide and Transwell assays, cell cycle and apoptosis rate analyses and western blotting were conducted to investigate the effects of PZH on the proliferation rate of ovarian cancer cells and its potential molecular pathway. The results showed that PZH inhibits the proliferation of the human ovarian cancer OVCAR-3 cell line by blocking the progression of the cell cycle from the G1 to S phase, however, PZH did not induce OVCAR-3 cell apoptosis. Increased PZH concentration may downregulate the expression of AKT, phosphorylated (p)-AKT, mammalian target of rapamycin (mTOR) and p-mTOR proteins in the OVCAR-3 cell line. In addition, it was observed that PZH may suppress the protein expression of cyclin-dependent kinase (CDK)4 and CDK6. Overall, the results of the present study indicated that PZH may inhibit ovarian cancer cell proliferation by modulating the activity of the AKT-mTOR pathway.
doi:10.3892/ol.2014.1989
PMCID: PMC4049676  PMID: 24932287
Pien Tze Huang; ovarian cancer; proliferation; cell cycle
12.  Tracing Fasting Glucose Fluxes with Unstressed Catheter Approach in Streptozotocin Induced Diabetic Rats 
Journal of Diabetes Research  2014;2014:743798.
Objective. Blood glucose concentrations of type 1 diabetic rats are vulnerable, especially to stress and trauma. The present study aimed to investigate the fasting endogenous glucose production and skeletal muscle glucose uptake of Streptozotocin induced type 1 diabetic rats using an unstressed vein and artery implantation of catheters at the tails of the rats as a platform. Research Design and Methods. Streptozotocin (65 mg·kg−1) was administered to induce type 1 diabetic state. The unstressed approach of catheters of vein and artery at the tails of the rats was established before the isotope tracer injection. Dynamic measurement of fasting endogenous glucose production was assessed by continuously infusing stable isotope [6, 6-2H2] glucose, while skeletal muscle glucose uptake by bolus injecting radioactively labeled [1-14C]-2-deoxy-glucose. Results. Streptozotocin induced type 1 diabetic rats displayed polydipsia, polyphagia, and polyuria along with overt hyperglycemia and hypoinsulinemia. They also had enhanced fasting endogenous glucose production and reduced glucose uptake in skeletal muscle compared to nondiabetic rats. Conclusions. The dual catheters implantation at the tails of the rats together with isotope tracers injection is a save time, unstressed, and feasible approach to explore the glucose metabolism in animal models in vivo.
doi:10.1155/2014/743798
PMCID: PMC3977083  PMID: 24772449
13.  The mediating role of self-efficacy in the relationship between Big five personality and depressive symptoms among Chinese unemployed population: a cross-sectional study 
BMC Psychiatry  2014;14:61.
Background
Besides the rapid growth of economy, unemployment becomes a severe socio-economic problem in China. The huge population base in China makes the unemployed population a tremendously huge number. However, health status of unemployed population was ignored and few studies were conducted to describe the depressive symptoms of unemployed individuals in China. This study aims to examine the relationship between Big five personality and depressive symptoms and the mediating role of self-efficacy in this relationship.
Methods
This cross-sectional study was performed during the period of July to September 2011. Questionnaires consisting of the Center for Epidemiologic Studies Depression Scale (CES-D), the Big Five Inventory (BFI) and the General Self-efficacy Scale (GSE), as well as demographic factors, were used to collect information of unemployed population. A total of 1,832 individuals (effective response rate: 73.28%) became our subjects. Hierarchical linear regression analyses were performed to explore the mediating role of self-efficacy.
Results
The prevalence of depressive symptoms was 67.7% among Chinese unemployed individuals. After adjusting for demographic characteristics, extraversion, agreeableness and conscientiousness were all negatively associated with depressive symptoms whereas neuroticism was positively associated with depressive symptoms. The proportion of mediating effect of self-efficacy in the relationship between extraversion/agreeableness/conscientiousness/neuroticism and depressive symptoms was 25.42%, 10.91%, 32.21% and 36.44%, respectively. Self-efficacy is a mediator in the relationship between extraversion/agreeableness/conscientiousness/neuroticism and depressive symptoms.
Conclusion
Self-efficacy partially mediated the relationship between Big five personality and depressive symptoms among Chinese unemployed individuals. Interventions that focus on both individuals’ personality and self-efficacy may be most successful to reduce depressive symptoms of unemployed individuals.
doi:10.1186/1471-244X-14-61
PMCID: PMC3976156  PMID: 24581332
Depressive symptoms; Big five personality; Self-efficacy; Unemployed
14.  Enzymatic transamination of d-kynurenine generates kynurenic acid in rat and human brain 
Journal of neurochemistry  2012;120(6):1026-1035.
In the mammalian brain, the α7 nicotinic and NMDA receptor antagonist kynurenic acid is synthesized by irreversible enzymatic transamination of the tryptophan metabolite l-kynure-nine. d-kynurenine, too, serves as a bioprecursor of kynurenic acid in several organs including the brain, but the conversion is reportedly catalyzed through oxidative deamination by d-aminoacid oxidase. Using brain and liver tissue homogenates from rats and humans, and conventional incubation conditions for kynurenine aminotransferases, we show here that kynurenic acid production from d-kynurenine, like the more efficient kynurenic acid synthesis from l-kynurenine, is blocked by the aminotransferase inhibitor amino-oxyacetic acid. In vivo, focal application of 100 µM d-kynurenine by reverse microdialysis led to a steady rise in extracellular kynurenic acid in the rat striatum, causing a 4-fold elevation after 2 h. Attesting to functional significance, this increase was accompanied by a 36% reduction in extracellular dopamine. Both of these effects were duplicated by perfusion of 2 µM l-kynurenine. Co-infusion of amino-oxyacetic acid (2 mM) significantly attenuated the in vivo effects of d-kynurenine and essentially eliminated the effects of l-kynurenine. Thus, enzymatic transamination accounts in part for kynurenic acid synthesis from d-kynurenine in the brain. These results are discussed with regard to implications for brain physiology and pathology.
doi:10.1111/j.1471-4159.2012.07653.x
PMCID: PMC3929305  PMID: 22224417
α7 nicotinic receptor; aminotransferases; dopamine; microdialysis; NMDA receptor; schizophrenia
15.  The Astrocyte-Derived α7 Nicotinic Receptor Antagonist Kynurenic Acid Controls Extracellular Glutamate Levels in the Prefrontal Cortex 
The cognitive deficits seen in schizophrenia patients are likely related to abnormal glutamatergic and cholinergic neurotransmission in the prefrontal cortex. We hypothesized that these impairments may be secondary to increased levels of the astrocyte-derived metabolite kynurenic acid (KYNA), which inhibits α7 nicotinic acetylcholine receptors (α7AChR) and may thereby reduce glutamate release. Using in vivo microdialysis in unanesthetized rats, we show here that nanomolar concentrations of KYNA, infused directly or produced in situ from its bioprecursor kynurenine, significantly decrease extracellular glutamate levels in the prefrontal cortex. This effect was prevented by the systemic administration of galantamine (3 mg/kg) but not by donepezil (2 mg/kg), indicating that KYNA blocks the allosteric potentiating site of the α7AChR, which recognizes galantamine but not donepezil as an agonist. In separate rats, reduction of prefrontal KYNA formation by (S)-4-ethylsulfonyl benzoylalanine, a specific inhibitor of KYNA synthesis, caused a significant elevation in extracellular glutamate levels. Jointly, our results demonstrate that fluctuations in endogenous KYNA formation bidirectionally influence cortical glutamate concentrations. These findings suggest that selective attenuation of cerebral KYNA production, by increasing glutamatergic tone, might improve cognitive function in individuals with schizophrenia.
doi:10.1007/s12031-009-9235-2
PMCID: PMC3929341  PMID: 19690987
Cognition; Donepezil; Galantamine; Kynurenine; Microdialysis; Prefrontal cortex
16.  Coupling-induced synchronization in multicellular circadian oscillators of mammals 
Cognitive Neurodynamics  2012;7(1):59-65.
In mammals, circadian rhythms are controlled by the neurons located in the suprachiasmatic nucleus (SCN) of the hypothalamus. Each neuron in the SCN contains an autonomous molecular clock. The fundamental question is how the individual cellular oscillators, expressing a wide range of periods, interact and assemble to achieve phase synchronization. Most of the studies carried out so far emphasize the crucial role of the periodicity imposed by the light-dark cycle in neuronal synchronization. However, in natural conditions, the interaction between the SCN neurons is non-negligible and coupling between cells in the SCN is achieved partly by neurotransmitters. In this paper, we use a model of nonidentical, globally coupled cellular clocks considered as Goodwin oscillators. We mainly study the synchronization induced by coupling from an analytical way. Our results show that the role of the coupling is to enhance the synchronization to the external forcing. The conclusion of this paper can help us better understand the mechanism of circadian rhythm.
doi:10.1007/s11571-012-9218-9
PMCID: PMC3538099  PMID: 24427191
Circadian rhythm; Clock; Synchronization; Self-sustained oscillator
17.  A Test of Rensch’s Rule in Greater Horseshoe Bat (Rhinolophus ferrumequinum) with Female-Biased Sexual Size Dimorphism 
PLoS ONE  2014;9(1):e86085.
Sexual size dimorphism (SSD) is widespread within the animal kingdom. Rensch’s rule describes a relationship between SSD and body size: SSD increases with body size when males are the larger sex, and decreases with body size when females are the larger sex. Rensch’s rule is well supported for taxa that exhibit male-biased SSD but patterns of allometry among taxa with female-biased size dimorphism are mixed, there is evidence both for and against the rule. Furthermore, most studies have investigated Rensch’s rule across a variety of taxa; but among-population studies supporting Rensch’s rule are lacking, especially in taxa that display only slight SSD. Here, we tested whether patterns of intraspecific variation in SSD in greater horseshoe bats conform to Rensch’s rule, and evaluated the contribution of latitude to Rensch’s rule. Our results showed SSD was consistently female-biased in greater horseshoe bats, although female body size was only slightly larger than male body size. The slope of major axis regression of log10 (male) on log10 (female) was significantly different from 1. Forearm length for both sexes of greater horseshoe bats was significantly negatively correlated with latitude, and males displayed a slightly but nonsignificant steeper latitudinal cline in body size than females. We suggest that variation in patterns of SSD among greater horseshoe bat populations is consistent with Rensch’s rule indicating that males were the more variable sex. Males did not have a steeper body size–latitude relationship than females suggesting that sex-specific latitudinal variation in body size may not be an important contributing factor to Rensch’s rule. Future research on greater horseshoe bats might best focus on more comprehensive mechanisms driving the pattern of female-biased SSD variation.
doi:10.1371/journal.pone.0086085
PMCID: PMC3896443  PMID: 24465886
18.  Exploring genome-wide DNA methylation profiles altered in hepatocellular carcinoma using Infinium HumanMethylation 450 BeadChips 
Epigenetics  2013;8(1):34-43.
Hepatocellular carcinoma (HCC) incidence has increased in the US and also has one of the fastest growing death rates of any cancer. The purpose of the current study was to discover novel genome-wide aberrant DNA methylation patterns in HCC tumors that are predominantly HCV-related. Infinium HumanMethylation 450K BeadChip arrays were used to examine genome-wide DNA methylation profiles in 66 pairs of HCC tumor and adjacent non-tumor tissues. After Bonferroni adjustment, a total of 130,512 CpG sites significantly differed in methylation level in tumor compared with non-tumor tissues, with 28,017 CpG sites hypermethylated and 102,495 hypomethylated in tumor tissues. Absolute tumor/non-tumor methylation differences ≥ 20% were found in 24.9% of the hypermethylated and 43.1% of the hypomethylated CpG sites; almost 10,000 CpG sites have ≥ 30% DNA methylation differences. Most (60.1%) significantly hypermethylated CpG sites are located in CpG islands, with 21.6% in CpG shores and 3.6% in shelves. In contrast, only a small proportion (8.2%) of significantly hypomethylated CpG sites are situated in islands, while most are found in open sea (60.2%), shore (17.3%) or shelf (14.3%) regions. A total of 2,568 significant CpG sites (2,441 hypermethylated and 127 hypomethylated) covering 589 genes are located within 684 differentially methylated regions defined as regions with at least two significant CpG sites displaying > 20% methylation differences in the same direction within 250-bp. The top 500 significant CpG sites can significantly distinguish HCC tumor from adjacent tissues with one misclassification. Within adjacent non-tumor tissues, we also identified 75 CpG sites significantly associated with gender, 228 with HCV infection, 17,207 with cirrhosis, and 56 with both HCV infection and cirrhosis after multiple comparisons adjustment. Aberrant DNA methylation profiles across the genome were identified in tumor tissues from US HCC cases that are predominantly related to HCV infection. These results demonstrate the significance of aberrant DNA methylation in HCC tumorigenesis.
doi:10.4161/epi.23062
PMCID: PMC3549879  PMID: 23208076
genome-wide; DNA methylation; alterations; hepatocellular carcinoma; 450K BeadChips
19.  Recent Advances in Mass Spectrometry for the Identification of Neuro-chemicals and their Metabolites in Biofluids 
Current Neuropharmacology  2013;11(4):436-464.
Recently, mass spectrometric related techniques have been widely applied for the identification and quantification of neurochemicals and their metabolites in biofluids. This article presents an overview of mass spectrometric techniques applied in the detection of neurological substances and their metabolites from biological samples. In addition, the advances of chromatographic methods (LC, GC and CE) coupled with mass spectrometric techniques for analysis of neurochemicals in pharmaceutical and biological samples are also discussed.
doi:10.2174/1570159X11311040007
PMCID: PMC3744906  PMID: 24381533
Neurochemicals; LC-MS; GC-MS; CE-MS; MALDI-MS.
20.  Short- and long-term outcomes of definitive chemoradiotherapy in patients with esophageal carcinoma aged ≥75 years 
Molecular and Clinical Oncology  2013;2(2):297-301.
The most relevant treatment modalities in elderly patients with esophageal carcinoma (EC) remain a subject of debate. Combined definitive chemoradiotherapy (CRT) is currently widely accepted as a non-surgical treatment for esophageal cancer. However, elderly patients were excluded from the majority of studies on CRT, or the proportion of elderly patients was relatively low in those studies and the number of available studies on the treatment of EC patients aged ≥75 years is limited. The aim of the present retrospective study was to analyze the safety and efficacy of CRT in patients aged ≥75 years in order to assess the short- and long-term outcomes of CRT for elderly patients with EC. In this study, based on further refinement of patient age groups and analysis of the Charlson comorbidity score, we performed a statistical analysis of factors such as short-term response, long-term survival and toxicity reactions. The results of the analysis indicated that the treatment of patients with EC aged ≥75 years with radiotherapy (RT) and chemotherapy was effective. However, we recommend that customized treatment is based on the stratification of patients into different age groups and the Charlson score, as for patients aged ≥80 years a lower-dose therapy may be more beneficial and for patients aged ≥85 years definitive CRT should be administered with greater caution.
doi:10.3892/mco.2013.235
PMCID: PMC3917785  PMID: 24649350
esophageal carcinoma; definitive chemoradiotherapy; elderly
21.  Effects of Electroacupuncture on PGC-1α Expression in Brown Adipose Tissue 
The inducible coactivator PGC-1α plays master regulator in mitochondrial biogenesis and thermogenesis in brown adipose tissues (BATs). BAT is a natural antiobesity organ which dissipates chemical energy in the form of heat through specialized mitochondrial protein UCP-1. Eletroacupuncture (EA) has been widely used as an alternative treatment for obesity and its related disorders such as type 2 diabetes. The molecular mechanism of electroacupuncture on treatment of obesity is still unclear. We hypothesized that electroacupuncture induced PGC-1α expression to increase the energy expenditure in BAT. Rats were randomly divided into control group and electroacupuncture treatment group. We investigated the effects of electroacupuncture at Zusanli (ST36) acupoint on the expressions of PGC-1α and its associated genes in the BAT of rats using real-time PCR and western blotting. We found that electroacupuncture effectively induces the expression of PGC-1α and UCP-1 by 4-fold and 5-fold in the BAT of rats, respectively. Our results indicated that the molecular mechanism of electroacupuncture for the treatment of obesity may be, or at least partially, through induction of both PGC-1α and UCP-1 expressions to increase energy expenditure in BAT.
doi:10.1155/2013/625104
PMCID: PMC3892755  PMID: 24489587
22.  Refractive Error, Visual Acuity and Causes of Vision Loss in Children in Shandong, China. The Shandong Children Eye Study 
PLoS ONE  2013;8(12):e82763.
Purpose
To examine the prevalence of refractive errors and prevalence and causes of vision loss among preschool and school children in East China.
Methods
Using a random cluster sampling in a cross-sectional school-based study design, children with an age of 4–18 years were selected from kindergartens, primary schools, and junior and senior high schools in the rural Guanxian County and the city of Weihai. All children underwent a complete ocular examination including measurement of uncorrected (UCVA) and best corrected visual acuity (BCVA) and auto-refractometry under cycloplegia. Myopia was defined as refractive error of ≤−0.5 diopters (D), high myopia as ≤−6.0D, and amblyopia as BCVA ≤20/32 without any obvious reason for vision reduction and with strabismus or refractive errors as potential reasons.
Results
Out of 6364 eligible children, 6026 (94.7%) children participated. Prevalence of myopia (overall: 36.9±0.6%;95% confidence interval (CI):36.0,38.0) increased (P<0.001) from 1.7±1.2% (95%CI:0.0,4.0) in the 4-years olds to 84.6±3.2% (95%CI:78.0,91.0) in 17-years olds. Myopia was associated with older age (OR:1.56;95%CI:1.52,1.60;P<0.001), female gender (OR:1.22;95%CI:1.08,1.39;P = 0.002) and urban region (OR:2.88;95%CI:2.53,3.29;P<0.001). Prevalence of high myopia (2.0±0.2%) increased from 0.7±0.3% (95%CI:0.1,1.3) in 10-years olds to 13.9±3.0 (95%CI:7.8,19.9) in 17-years olds. It was associated with older age (OR:1.50;95%CI:1.41,1.60;P<0.001) and urban region (OR:3.11;95%CI:2.08,4.66);P<0.001). Astigmatism (≥0.75D) (36.3±0.6%;95%CI:35.0,38.0) was associated with older age (P<0.001;OR:1.06;95%CI:1.04,1.09), more myopic refractive error (P<0.001;OR:0.94;95%CI:0.91,0.97) and urban region (P<0.001;OR:1.47;95%CI:1.31,1.64). BCVA was ≤20/40 in the better eye in 19 (0.32%) children. UCVA ≤20/40 in at least one eye was found in 2046 (34.05%) children, with undercorrected refractive error as cause in 1975 (32.9%) children. Amblyopia (BCVA ≤20/32) was detected in 44 (0.7%) children (11 children with bilateral amblyopia).
Conclusions
In coastal East China, about 14% of the 17-years olds were highly myopic, and 80% were myopic. Prevalence of myopia increased with older age, female gender and urban region. About 0.7% of pre-school children and school children were amblyopic.
doi:10.1371/journal.pone.0082763
PMCID: PMC3871613  PMID: 24376575
23.  Interoperative fundus image and report sharing in compliance with integrating the healthcare enterprise conformance and web access to digital imaging and communication in medicine persistent object protocol 
AIM
To address issues in interoperability between different fundus image systems, we proposed a web eye-picture archiving and communication system (PACS) framework in conformance with digital imaging and communication in medicine (DICOM) and health level 7 (HL7) protocol to realize fundus images and reports sharing and communication through internet.
METHODS
Firstly, a telemedicine-based eye care work flow was established based on integrating the healthcare enterprise (IHE) Eye Care technical framework. Then, a browser/server architecture eye-PACS system was established in conformance with the web access to DICOM persistent object (WADO) protocol, which contains three tiers.
RESULTS
In any client system installed with web browser, clinicians could log in the eye-PACS to observe fundus images and reports. Multipurpose internet mail extensions (MIME) type of a structured report is saved as pdf/html with reference link to relevant fundus image using the WADO syntax could provide enough information for clinicians. Some functions provided by open-source Oviyam could be used to query, zoom, move, measure, view DICOM fundus images.
CONCLUSION
Such web eye-PACS in compliance to WADO protocol could be used to store and communicate fundus images and reports, therefore is of great significance for teleophthalmology.
doi:10.3980/j.issn.2222-3959.2013.06.24
PMCID: PMC3874532  PMID: 24392341
picture archiving and communication system; teleophthalmology; integrating the healthcare enterprise; web access to DICOM persistent object
24.  Correlation and Interaction Visualization of Altmetric Indicators Extracted From Scholarly Social Network Activities: Dimensions and Structure 
Background
Citation counts for peer-reviewed articles and the impact factor of journals have long been indicators of article importance or quality. In the Web 2.0 era, growing numbers of scholars are using scholarly social network tools to communicate scientific ideas with colleagues, thereby making traditional indicators less sufficient, immediate, and comprehensive. In these new situations, the altmetric indicators offer alternative measures that reflect the multidimensional nature of scholarly impact in an immediate, open, and individualized way. In this direction of research, some studies have demonstrated the correlation between altmetrics and traditional metrics with different samples. However, up to now, there has been relatively little research done on the dimension and interaction structure of altmetrics.
Objective
Our goal was to reveal the number of dimensions that altmetric indicators should be divided into and the structure in which altmetric indicators interact with each other.
Methods
Because an article-level metrics dataset is collected from scholarly social media and open access platforms, it is one of the most robust samples available to study altmetric indicators. Therefore, we downloaded a large dataset containing activity data in 20 types of metrics present in 33,128 academic articles from the application programming interface website. First, we analyzed the correlation among altmetric indicators using Spearman rank correlation. Second, we visualized the multiple correlation coefficient matrixes with graduated colors. Third, inputting the correlation matrix, we drew an MDS diagram to demonstrate the dimension for altmetric indicators. For correlation structure, we used a social network map to represent the social relationships and the strength of relations.
Results
We found that the distribution of altmetric indicators is significantly non-normal and positively skewed. The distribution of downloads and page views follows the Pareto law. Moreover, we found that the Spearman coefficients from 91.58% of the pairs of variables indicate statistical significance at the .01 level. The non-metric MDS map divided the 20 altmetric indicators into three clusters: traditional metrics, active altmetrics, and inactive altmetrics. The social network diagram showed two subgroups that are tied to each other but not to other groups, thus indicating an intersection between altmetrics and traditional metric indicators.
Conclusions
Altmetrics complement, and most correlate significantly with, traditional measures. Therefore, in future evaluations of the social impact of articles, we should consider not only traditional metrics but also active altmetrics. There may also be a transfer phenomenon for the social impact of academic articles. The impact transfer path has transfer, or intermediate, stations that transport and accelerate article social impact from active altmetrics to traditional metrics and vice versa. This discovery will be helpful to explain the impact transfer mechanism of articles in the Web 2.0 era. Hence, altmetrics are in fact superior to traditional filters for assessing scholarly impact in multiple dimensions and in terms of social structure.
doi:10.2196/jmir.2707
PMCID: PMC3841360  PMID: 24275693
altmetrics; article-level metrics; scholarly social network tools; indicator; dimension; structure
25.  Surveillance and Correlation of Antimicrobial Usage and Resistance of Pseudomonas aeruginosa: A Hospital Population-Based Study 
PLoS ONE  2013;8(11):e78604.
This retrospective study evaluated trends and association between resistance of Pseudomonas aeruginosa isolated from patients with hospital-acquired infections (HAIs) and hospital antimicrobial usage from 2003 through 2011 in a tertiary care hospital in northeast China. HAI was defined as occurrence of infection after hospital admission, without evidence that infection was present or incubating (≦48 h) on admission. In vitro susceptibilities were determined by disk diffusion test and susceptibility profiles were determined using zone diameter interpretive criteria, as recommended by Clinical and Laboratory Standards Institute (CLSI). Data on usage of various antimicrobial agents, expressed as defined daily dose (DDD) per 1,000 patients-days developed by WHO Anatomical Therapeutical Chemical (ATC)/DDD index 2011, were collected from hospital pharmacy computer database. Most of 747 strains of P. aeruginosa were collected from respiratory samples (201 isolates, 26.9%), blood (179, 24.0%), secretions and pus (145, 19.4%) over the years. Time series analysis demonstrated a significant increase in resistance rates of P. aeruginosa to ticarcillin/clavulanic acid, piperacillin/tazobactam, cefoperazone/sulbactam, piperacillin, imipenem, meropenem, ceftazidime, cefepime, ciprofloxacin, and levofloxacin except aminoglycosides over time in the hospital (P<0.001). The rates of carbapenem-resistant P. aeruginosa (CRPA) isolated from patients with HAIs were 14.3%, 17.1%, 21.1%, 24.6%, 37.0%, 48.8%, 56.4%, 51.2%, and 54.1% over time. A significant increase in usage of anti-pseudomonal carbapenems (P<0.001) was seen. ARIMA models demonstrated that anti-pseudomonal carbapenems usage was strongly correlated with the prevalence of imipenem and meropenem-resistant P. aeruginosa (P<0.001). Increasing of quarterly CRPA was strongly correlated at one time lag with quarterly use of anti-pseudomonal carbapenems (P<0.001). Our data demonstrated positive correlation between anti-pseudomonal antimicrobial usage and P. aeruginosa resistance to several classes of antibiotics, but not all antimicrobial agents in the hospital.
doi:10.1371/journal.pone.0078604
PMCID: PMC3826718  PMID: 24250801

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